rs45517932

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_138694.4(PKHD1):c.5125C>T(p.Leu1709Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00598 in 1,614,206 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 42 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 6.54

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain IPT/TIG 12; atypical (size 84) in uniprot entity PKHD1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_138694.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0142250955).

BS2

High Homozygotes in GnomAdExome4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.5125C>T	p.Leu1709Phe	missense_variant	Exon 32 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.5125C>T	p.Leu1709Phe	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.5125C>T	p.Leu1709Phe	missense_variant	Exon 32 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00636

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00282

AC:

709

AN:

251342

Hom.:

AF XY:

0.00297

AC XY:

404

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00528

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00623

AC:

9103

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00603

AC XY:

4387

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00770

Gnomad4 OTH exome

AF:

0.00654

GnomAD4 genome

AF:

0.00364

AC:

554

AN:

152336

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00636

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00362

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00240

AC:

291

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2020	This variant is associated with the following publications: (PMID: 24162162, 30809968, 19940839, 20413436, 16133180, 15805161, 15108277, 12874454, 12846734) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	PKHD1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 06, 2023	BS1 -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2022	Variant summary: PKHD1 c.5125C>T (p.Leu1709Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251342 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0028 vs 0.0071), allowing no conclusion about variant significance. However, this variant was observed in high allele frequency (as high as 1.5%) in healthy controls in multiple publications and classified as polymorphism (Rossetti_2003, Bergmann_2014, Sharp_2005, Losekoot_2005). c.5125C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Gunay-Aygun_2010, Denamur_2010, Bullich_2018). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four have classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.61

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.95

MPC

0.39

ClinPred

0.033

GERP RS

4.7

Varity_R

0.12

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over